A hepatic zonation chip with an oxygen concentration gradient embracing the spatial distribution of metabolic function.

IF 8.2 2区 医学 Q1 ENGINEERING, BIOMEDICAL
Min Kyeong Kim, Kyurim Paek, Kyungwon Park, Sungho Tak, Kyuhwan Na, Jung Hoon Choi, Sang-Mi Woo, HanByeol Kim, Yeo Min Yoon, Seok Chung, Jeong Ah Kim
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Abstract

The development of hepaticin vitromodels that replicate the physiological characteristics of liver tissue is critical for the accurate translation of drug test results. Current models often fail to mimic the spatial zonation by an oxygen concentration gradient in the hepatic acinus, limiting their ability to predict drug-induced hepatotoxicity. This study aimed to develop a hepatic zonation chip (H-chip) that replicates the oxygen gradient of the hepatic acinus, enhancing physiological relevance for drug testing applications. The H-chip was fabricated with a circular microfabricated chip chamber covered by oxygen-impermeable glass substrates, generating a radial oxygen concentration gradient through oxygen consumption by hepatic cells. This gradient mimics the portal-to-central oxygen distribution observedin vivo, enabling zone-specific hepatic functionality. We showed that the H-chip successfully reproduced the oxygen gradients found in thein vivohepatic acinus along with corresponding cell cytocompatibility of hepatic cells. Notably, pericentral-specific hepatic functionality increased in the H-chip and decreased in the normoxia chip (N-chip). Spatial transcriptomic analysis revealed heterogeneous gene expression patterns aligned with local metabolic functions in each zone across the H-chip. Furthermore, toxicity evaluation of acetaminophen, a representative drug known for its spatial hepatotoxicity, revealed increased zonation-specific sensitivity in the H-chip, linked to elevated cytochrome P450 gene expression and toxic metabolite formation. These findings highlight the ability of the H-chip to replicate hepatic zonal characteristics, thus providing a robust platform for evaluating hepatotoxicity in drug testing. This platform promises to advance safer and more effective drug development by enabling more physiologically relevant assessments.

一种包含代谢功能空间分布的氧浓度梯度的肝脏分区芯片。
建立能够复制肝组织生理特征的肝脏体外模型对于药物测试结果的准确翻译至关重要。目前的模型往往不能通过肝腺泡中的氧浓度梯度模拟空间分区,限制了它们预测药物引起的肝毒性的能力。本研究旨在开发一种肝分区芯片(H-chip),该芯片可以复制肝腺泡的氧梯度,增强药物测试应用的生理相关性。h芯片是由一个圆形的微晶片腔制成的,覆盖着不透氧的玻璃衬底,通过肝细胞的氧气消耗产生径向氧浓度梯度。这种梯度模拟了在体内观察到的门户到中心的氧气分布,实现了特定区域的肝脏功能。我们证明了h芯片成功地复制了肝腺泡体内的氧梯度以及相应的肝细胞细胞相容性。值得注意的是,在h芯片中,中心周围特异性肝脏功能增加,而在常氧芯片(n芯片)中,肝脏功能下降。空间转录组学分析显示,在h芯片的每个区域,异质基因表达模式与局部代谢功能一致。此外,对乙酰氨基酚(一种以其空间肝毒性而闻名的代表性药物)的毒性评估显示,h芯片的区特异性敏感性增加,与细胞色素P450基因表达升高和毒性代谢物形成有关。这些发现强调了h芯片复制肝分区特征的能力,为药物测试中评估肝毒性提供了一个强大的平台。该平台承诺通过进行更多与生理相关的评估来推进更安全、更有效的药物开发。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biofabrication
Biofabrication ENGINEERING, BIOMEDICAL-MATERIALS SCIENCE, BIOMATERIALS
CiteScore
17.40
自引率
3.30%
发文量
118
审稿时长
2 months
期刊介绍: Biofabrication is dedicated to advancing cutting-edge research on the utilization of cells, proteins, biological materials, and biomaterials as fundamental components for the construction of biological systems and/or therapeutic products. Additionally, it proudly serves as the official journal of the International Society for Biofabrication (ISBF).
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